Characterization of the response to kappa opiate agonist Salvinorin A in healthy humans Background: Salvinorin A (SA) is the active compound derived from the leaves of the hallucinogenic plant Salvia divinorum, which has been used for centuries in traditional Mexican rituals. More recently, the recreational use of SA for its hallucinogenic effects is increasingly popular amongst young adults. However, there are no controlled data on the effects of SA in humans. SA is unique in being a highly selective agonist solely at the kappa opioid receptor (KOR) and presumably produces its psychotomimetic effects by agonism at this receptor. While there is increasing recognition and concern about the recreational use of SA, there are no controlled studies systematically characterizing its effects in humans. Aims: To characterize the dose-related behavioral, subjective, reinforcing, cognitive, physiological, neuroendocrine and psycho-physiological effects of inhaled SA in healthy humans. Research Design and Methods: 33 healthy subjects will be recruited from the community and after obtaining consent will be carefully screened for participation. Subjects will receive, on 3 separate test days, either placebo or one of two active SA doses (20,005g or 30,005g) through an inhaled route, in a double blind manner. Behavioral, subjective, cognitive and physiological data will be collected throughout each test day. Resting EEG will be obtained immediately after inhalation for 3 minutes with eyes closed. Behavioral measures will include the Clinician Administered Dissociative Symptoms Scale, the Psychotomimetic States Inventory, the Hallucinogen Rating Scale, and the Positive and Negative Syndrome Scale. Subjective effects will be measured on a Visual Analog Scale (VAS). Cognitive measures will include digits forward, digits backward and the letter number sequencing task. Physiological parameters (blood pressure, pulse rate, pulse oximetry) and pupil size will be measured. Blood will be sampled frequently for analysis of SA and plasma prolactin levels. Impact/Significance: The rates of recreational use of Salvinorin A have been rapidly increasing over the last few years and although not federally controlled, a growing number of states have passed legislation controlling its use. However, there is very limited published data on the effects induced by SA in humans. Thus, the growing concern about SA use coupled with the paucity of research in this area presents an urgent need to systematically characterize its dose related subjective, behavioral, cognitive and physiological effects in humans both from a public health as well as regulatory perspective. PUBLIC HEALTH RELEVANCE: There is increasing concern about the recreational use of the hallucinogenic drug Salvinorin A (SA) that is rapidly gaining popularity amongst young adults. The literature on the range effects induced by SA in humans is extremely limited and consists mainly of anecdotal reports from SA users. The lack of data in this area thus presents a compelling need to systematically characterize a wide range of dose related effects of this drug in humans.